Cilostazol Trumps Aspirin in Secondary Stroke Prevention

Caroline Cassels

March 09, 2010

March 9, 2010 (San Antonio, Texas) — The phosphodiesterase inhibitor cilostazol is more effective in secondary stroke prevention and has a significantly lower incidence of serious cerebral hemorrhage compared with aspirin (ASA) in patients with noncardioembolic cerebral infarction, new research suggests.

Presented here at a late-breaking scientific session during the International Stroke Conference 2010, the results of the head-to-head trial show that individuals treated with cilostazol were 25.7% less likely to have a stroke than their counterparts who received ASA.

Furthermore, patients in the cilostazol group were significantly less likely to have an intracerebral hemorrhage (ICH), subarachnoid hemorrhage, or hemorrhage requiring hospitalization compared with those in the ASA group.

In addition, said Dr. Shinohara, cilostazol had a superior safety profile, with significantly lower rates on the secondary composite endpoint of stroke, transient ischemic attack (TIA), angina pectoris, myocardial infarction (MI), heart failure, or hemorrhage requiring hospitalization.

"Based on these findings, we believe cilostazol should be considered as a potential treatment option for secondary stroke prevention in patients who can tolerate long-term administration of this drug, " principal investigator Yukito Shinohara, MD, Tachikawa Hospital in Tokyo, Japan, told Medscape Neurology.

Number Needed to Treat Unacceptably High

Dr. Yukito Shinohara

According to Dr. Shinohara, although ASA and other antiplatelet medications, such as clopidogrel, are effective in secondary stroke prevention, the number needed to treat to prevent a single event is unacceptably high — 26 to 28 patients for 3 years. Furthermore, he added, antiplatelet therapy also carries a significant risk for hemorrhagic adverse effects.

The first study of cilostazol — known as the Cilostazol Stroke Prevention Study (CSPS) — conducted by Dr. Shinohara and colleagues in Japan about 10 years ago demonstrated that the drug was more effective compared with placebo, with a low risk of bleeding.

This led to the current study, the CSPS-2, which pits the drug against ASA, the current standard of care for secondary stroke prevention.

The randomized, multicenter, double-blind, parallel-group study included 2757 noncardioembolic stroke patients from 278 centers. The study took place between December 2003 and December 2008.

Patients randomized to receive cilostazol received 100 mg twice daily, whereas subjects in the ASA group received 81 mg once daily. The duration of treatment lasted a minimum of 1 year and a maximum of 5 years.

Higher Rate of Nonserious Adverse Effects

The study's primary endpoint was occurrence of symptomatic stroke — cerebral infarction, ICH, or subarachnoid hemorrhage during the treatment period.

Secondary endpoints included recurrence of symptomatic cerebral infarction, occurrence of ischemic cerebrovascular event, death from any cause, or cluster of stroke, TIA, angina pectoris, MI, heart failure, or hemorrhage requiring hospitalization.

Stoke occurred in 82 of the 1337 cilostazol-treated patients, and 2 of these events were fatal during 2965.9 person-years. In the 1335 subjects in the ASA group, there were 119 strokes, including 3 deaths, during 3203.6 person-years.

Hemorrhagic stroke or hemorrhage requiring hospitalization occurred in 23 patients in the cilostazol group and 57 in the ASA group — a difference, said Dr. Shinohara, that was highly significant.

Although the rate of serious adverse events was lower in the cilostazol group, the drug fared worse compared with ASA with respect to adverse events other than bleeding, with higher rates of headache, diarrhea, palpitations, and dizziness. However, those in the ASA group had greater rates of hypertension and constipation.

Cheaper, Not Always Better

Dr. Shinohara pointed out that cilostazol is expensive — with a cost that is about 40 times greater than that of ASA. He said his group is currently conducting an economic analysis and subgroup analyses in the hope of characterizing optimal candidates for this treatment.

Currently, cilostazol is approved for use in the United States for the treatment of intermittent claudication, a common concern among patients with peripheral artery disease.

Asked by Medscape Neurology to comment on the study, Andrei Alexandrov, MD, director, Comprehensive Stroke Center, University of Alabama Hospital in Birmingham, said cilostazol may offer clinicians another potential treatment option.

"We need alternatives to aspirin because the main notion is that aspirin protects against stroke and heart attack but is it optimal? The answer is no. Aspirin is cheap, but cheap doesn't mean better. Aspirin protects against stroke, but it carries a risk of bleeding.

"We have clopidogrel and we have Aggrenox (a combination of ASA and dipyridamole), but in certain cases you run up against patients who can't take these, and cilostazol would give us another drug in our arsenal against secondary stroke," said Dr. Alexandrov.

The study was supported by Otsuka Pharmaceutical. Dr. Shinohara reports that he has received speaking fees and honoraria from Sanofi-Aventis, Mitsubishi Tanabe Pharma, Otsuka Pharmaceutical, Bayer HealthCare, Daiichi-Sankyo, and Kyorin Pharmaceutical and has served as a consultant and on the advisory board of Otsuka Pharmaceutical.

International Stroke Conference (ICS) 2010: Abstract 194. Presented February 26, 2010.

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